pH/GSH dual responsive nanosystem for nitric oxide generation enhanced type I photodynamic therapy

Tumor hypoxia diminishes the effectiveness of traditional type II photodynamic therapy(PDT)due to oxygen consumption.Type I PDT,which can operate independently of oxygen,is a viable option for treating hypoxic tumors.In this study,we have designed and synthesized JSK@PEG-IR820 NPs that are responsive to the tumor microenvironment(TME)to enhance type I PDT through glutathione(GSH)depletion.Our approach aims to expand the sources of therapeutic benefits by promoting the generation of superoxide radicals(O_(2)^(-).)while minimizing their consumption.The diisopropyl group within PEG-IR820 serves a dual purpose:it functions as a pH sensor for the disassembly of the NPs to release JSK and enhances intermolecular electron transfer to IR820,facilitating efficient O_(2)^(-).generation.Simultaneously,the release of JSK leads to GSH depletion,resulting in the generation of nitric oxide(NO).This,in turn,contributes to the formation of highly cytotoxic peroxynitrite(ONOO^(-).),thereby enhancing the therapeutic efficacy of these NPs.NIR-II fluorescence imaging guided therapy has achieved successful tumor eradication with the assistance of laser therapy.